Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2D6 and Tamoxifen Therapy
Matthew P. Goetz1, Katrin Sangkuhl2, Henk-Jan Guchelaar3, Matthias Schwab4,5,6, Michael Province7, Michelle Whirl-Carrillo2, W. Fraser Symmans8, Howard L. McLeod9, Mark J.
Ratain10, Hitoshi Zembutsu11, Andrea Gaedigk12, Ron H. van Schaik13,14, James N Ingle1, Kelly E. Caudle15, and Teri E. Klein2
1Department of Oncology, Mayo Clinic, Rochester, Minnesota, USA; Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota, USA
2Department of Biomedical Data Science, Stanford University, Stanford, California, USA
3Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden, The Netherlands 4Dr Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany
5Department of Clinical Pharmacology, University Hospital, Tuebingen, Germany 6Department of Pharmacy and Biochemistry, University of Tuebingen, Tuebingen, Germany 7Division of Statistical Genomics, Washington University School of Medicine, St. Louis, Missouri, USA 8Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA 9Moffitt Cancer Center, Tampa, FL USA 10Center for Personalized Therapeutics, University of Chicago, Chicago, IL 11Division of Human Genetics, National Cancer Center, Research Institute, Tokyo, Japan 12Division of Clinical Pharmacology, Toxicology & Therapeutic Innovation, Children’s Mercy Kansas City and Department of Pediatrics, University of Missouri-Kansas City, Kansas City, Missouri, USA 13International Expertcenter Pharmacogenetics, Dept Clinical Chemistry, Erasmus MC, Rotterdam, The Netherlands 14LKCH UMC Utrecht, The Netherlands 15Department of Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, TN, USA
Abstract
Tamoxifen is biotransformed by CYP2D6 to 4-hydroxytamoxifen and 4-hydroxy N-desmethyl tamoxifen (endoxifen), both with greater anti-estrogenic potency than the parent drug. Patients with certain CYP2D6 genetic polymorphisms and patients who receive strong CYP2D6 inhibitors exhibit lower endoxifen concentrations and a higher risk of disease recurrence in some studies of tamoxifen adjuvant therapy of early breast cancer. We summarize evidence from the literature and provide therapeutic recommendations for tamoxifen based on CYP2D6 genotype.
Corresponding Author: Matthew P. Goetz, M.D., Mayo Clinic, 200 First St. S.W., Rochester, MN 55905, Tel#1:507-284-3731, Fax:
HHS Public Access
Author manuscript
Clin Pharmacol Ther. Author manuscript; available in PMC 2019 May 01.
Published in final edited form as:
Clin Pharmacol Ther. 2018 May ; 103(5): 770–777. doi:10.1002/cpt.1007.
A uthor Man uscr ipt A uthor Man uscr ipt A uthor Man uscr ipt A uthor Man uscr ipt
INTRODUCTION
The purpose of this guideline is to provide clinicians information that will allow the interpretation of clinical CYP2D6 genotype tests so that the results can be used to guide prescribing of tamoxifen. Detailed guidelines for use of tamoxifen as well as analyses of cost effectiveness are beyond the scope of this document. The Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines are periodically updated at
www.cpicpgx.org/guidelines/.
FOCUSED LITERATURE REVIEW
A systematic literature review focused on CYP2D6 genotype and tamoxifen use (details in Supplement) was conducted.
GENE: CYP2D6
CYP2D6 is highly polymorphic with over 100 known allelic variants and subvariants identified (https://www.pharmvar.org/gene/CYP2D6); CYP2D6 Allele Definition Table (1)). CYP2D6 alleles have been extensively studied in multiple geographically, racially, and ethnically diverse groups and significant differences in allele frequencies have been
observed (CYP2D6 Frequency Table (1)). The most commonly reported alleles are categorized into functional groups as follows: Normal function (e.g., CYP2D6*1 and *2), decreased function (e.g., CYP2D6*9, *10, *17, and *41), and no function (e.g., CYP2D6*3,
*4, *5, *6) (2, 3). Because CYP2D6 is subject to gene deletions, duplications or
multiplications, many clinical laboratories also report copy number variations. CYP2D6*5 represents a gene deletion (no function allele) whereas gene duplications and multiplications are denoted by “xN” (e.g. CYP2D6*1xN with xN representing the number of CYP2D6 gene copies). Alleles carrying two or more normal function gene copies are categorized as alleles with increased function.
The combination of alleles is used to determine a patient’s diplotype (Table 1). Each functional status is assigned an activity value ranging from 0 to 1 (e.g. 0 for no function, 0.5 for decreased and 1.0 for normal function) (3). Table S1 describes the activity score values assigned to selected alleles. If an allele contains multiple copies of a functional gene, the value is multiplied by the number of copies present. Thus, the CYP2D6 activity score that is used to define CYP2D6 phenotype is the sum of the values assigned to each allele, which typically ranges from 0 to 3.0 but may exceed 3.0 in rare cases (3). See the CYP2D6 Diplotype-Phenotype Table (1) for a complete list of possible diplotypes and phenotype assignment.
The CYP2D6 activity score has been translated into the phenotype classification system for other CPIC guidelines (4, 5) as follows (CYP2D6 Allele Definition Table (1)): patients with an activity score (AS) of 0 are poor metabolizers (PMs), those with a score of 0.5 are considered intermediate metabolizers (IMs), and those with a score of 1.5 or 2.0 represent normal metabolizers (NMs). Patients with a score >2.0 are classified as ultrarapid
metabolizers (UMs). However, the activity score of 1.0 has less activity towards tamoxifen compared to those with an AS of 1. 5 or 2.0 and patients with an activity score of 1.0 may be
A uthor Man uscr ipt A uthor Man uscr ipt A uthor Man uscr ipt A uthor Man uscr ipt
classified as IMs by some reference laboratories. Thus, for this guideline, an activity score of 1.0 is classified as a CYP2D6 normal metabolizer or intermediate metabolizer, (Table 1).
This is in contrast to the classification used in previous guidelines (4, 5). A group of CYP2D6 experts are currently working to standardize the CYP2D6 genotype to phenotype translation system. Note that genotypes with an activity score of 1 are classified as NMs in the CYP2D6 Genotype to Phenotype Table (1) and CPIC will update the CPIC website and this table accordingly when the CYP2D6 genotype to phenotype standardization is complete (6). Because reference laboratories providing clinical CYP2D6 genotyping may use varying methods to assign phenotypes, it is advisable to note a patient’s CYP2D6 diplotype and to calculate an activity score before making therapeutic decisions about tamoxifen therapy.
Genetic Test Interpretation
Clinical laboratories rarely sequence the entire CYP2D6 gene or interrogate every known variant position. Instead, they typically test for variants that are used to determine high frequency allele haplotypes using the star-allele (*) nomenclature system, found at the Pharmacogene Variation Consortium website (http://www.PharmVar.org). Table S1 and tables found on the CPIC and PharmGKB website contain a list of CYP2D6 alleles, the specific combination of variants that can be used to determine the allele, functional status, and frequency across major ethnic populations as reported in the literature (1, 6).
The limitations of genetic testing as described here include: (1) rare variants may not be detected; (2) known star (*) alleles not tested for will not be reported, and instead, the allele will be reported as a *1 and *3 tests are not designed to detect unknown or de novo variants.
The Supplemental Material (Genetic Test Interpretation Section) contains additional information regarding CYP2D6 genetic test interpretation and phenotype assignment.
Available Genetic Test Options
See Supplemental Material and www.ncbi.nlm.nih.gov/gtr/ for more information on commercially available clinical testing options.
Incidental findings
Currently, there are no diseases or conditions that have been consistently linked to variation in the CYP2D6 gene independently of drug metabolism and response.
Other considerations
Chromosomal instability, i.e. loss of heterozygosity, is frequently observed in breast tumor tissue (7, 8). Genotype information derived from such tissue may therefore not accurately reflect the germline genotype that determines CYP2D6 activity in the liver where tamoxifen is metabolized. We therefore strongly recommend genotype testing be performed on non- tumor DNA isolated from a peripheral blood, or a saliva/buccal swab sample.
A uthor Man uscr ipt A uthor Man uscr ipt A uthor Man uscr ipt A uthor Man uscr ipt
DRUG: TAMOXIFEN
Background
About 65–75% of breast cancer expresses estrogen receptors (ER) or progesterone receptors (PR) (9). In this group of patients, endocrine therapy represents the most important treatment modality. Tamoxifen, a selective estrogen receptor modulator (SERM), has been studied and utilized in breast cancer for more than 40 years. When administered to women with ER- positive breast cancer for five years after surgery, tamoxifen almost halves the annual recurrence rate and reduces the breast cancer mortality rate by one-third in both pre- and post-menopausal women (10). While tamoxifen has multiple Food and Drug Administration (FDA) approvals for both the prevention and treatment of premenopausal and
postmenopausal breast cancer, tamoxifen's continued importance is reflected by its status as the only hormonal agent approved by the FDA for the prevention of premenopausal breast cancer, the treatment of ductal carcinoma in situ, and the adjuvant and metastatic treatment of premenopausal invasive breast cancer.
The pharmacology of tamoxifen is complex. Tamoxifen is a weak anti-estrogen that is extensively metabolized, and its metabolites exhibit similar, less, or more potent anti- estrogenic activity (11, 12). Furthermore, tamoxifen can exhibit either antiestrogenic or pro- estrogenic properties, depending on the target tissue and the presence or absence of co- activators or co-repressors (13, 14).
Tamoxifen undergoes extensive primary and secondary liver metabolism by cytochrome P450 enzymes via two major pathways: N-demethylation and 4-hydroxylation (Figure 1).
The predominant metabolic pathway (considered to contribute to over 90% of tamoxifen metabolism) is the demethylation of tamoxifen to N-desmethyltamoxifen primarily mediated by CYP3A4 (15), followed by CYP2D6-mediated oxidation to 4-hydroxy-N-
desmethyltamoxifen (endoxifen) (16). A minor metabolic pathway is hydroxylation of tamoxifen (mediated mainly by CYP2D6 but also catalyzed by CYP3A4 and CYP2C19) to 4-hydroxytamoxifen (4HT), which can then be further metabolized to endoxifen (17, 18).
While tamoxifen and its metabolites undergo glucuronidation and sulfation, no consistent effect of pharmacogenetic variation in any of the UGT or SULT isoforms on either tamoxifen pharmacokinetics or clinical outcomes has been observed to date.
The hydroxylation of either tamoxifen or N-desmtheyltamoxifen is considered to bioactivate tamoxifen. Both 4HT and endoxifen exhibit nearly 100-fold greater anti-estrogenic potency than the parent drug (11, 19–24). Maximum inhibition of estrogen-induced stimulation and ER transcription is achieved with endoxifen concentrations of ranging between 100–1000 nM (11). However, even low Z-endoxifen levels were necessary to block estrogen-mediated cell growth in models mimicking estrogen concentrations of pre- or postmenopausal women that were treated with tamoxifen and its metabolites (25, 26).
Both inter- and intra-individual variation in the concentration of tamoxifen and its
metabolites have been described (16, 22, 27–29). As it relates to the active metabolites, 4HT concentrations are low, typically <5 nM (17, 22) and the role of interpatient variability in 4HT as it relates to breast cancer outcomes is not well understood. In contrast, endoxifen
A uthor Man uscr ipt A uthor Man uscr ipt A uthor Man uscr ipt A uthor Man uscr ipt
plasma concentrations are up to 10 fold higher than 4HT, exhibiting substantial variability (17, 22, 30). Patients with low CYP2D6 enzyme activity, as a result of CYP2D6 genetic polymorphisms or the co-administration of strong CYP2D6 inhibitors, exhibit significantly lower endoxifen concentrations when treated with tamoxifen (22, 31).
Clinical studies to evaluate the association between endoxifen concentrations and CYP2D6 polymorphisms with tamoxifen outcome have yielded conflicting results. Initial (32) and follow-up data (33, 34) demonstrated that CYP2D6 PMs had an approximately two- to three-fold higher risk of breast cancer recurrence (compared to CYP2D6 NMs) and led an FDA special emphasis panel to recommend a tamoxifen label change to incorporate data that CYP2D6 genotype was an important biomarker associated with tamoxifen efficacy (35).
However, this label change was not implemented because of conflicting data from secondary analyses of 5 year tamoxifen prospective trials including ATAC (36), BIG1-98 (37), and ABCSG 8 (38). Multiple other studies were summarized in a meta-analysis that
demonstrated an association between CYP2D6 genotype and disease-free survival but only in patients that received tamoxifen as adjuvant therapy at a dose of 20 mg/day for five years (39).
Regarding the role of measurement of endoxifen concentrations, Madlensky et al identified an association between low endoxifen (lowest quintile) and recurrence (40). In a separate study of premenopausal patients, Saldores et al demonstrated similar findings that patients with low endoxifen concentrations (<14 nM) exhibited a higher risk for distant relapse or death compared with those with high concentrations (>35 nM) (41).
Given these conflicting data, a working group within CPIC was convened to review and summarize the strength of the data and to provide therapeutic recommendations for those patients in which CYP2D6 genotype is known and for whom adjuvant tamoxifen is recommended.
Linking genetic variability to variability in drug-related phenotypes
Endoxifen concentrations—There is substantial evidence linking CYP2D6 genotype with phenotypic variability in endoxifen concentrations. As outlined in Table S2, the evidence was considered uniformly strong that CYP2D6 PMs (AS=0) have lower plasma endoxifen concentrations among patients taking adjuvant tamoxifen compared to CYP2D6 NMs, and that reduced CYP2D6 activity (AS=0 to 1) is associated with lower plasma endoxifen concentrations among patients taking adjuvant tamoxifen compared to normal CYP2D6 activity. CYP2D6 genotype explains 34–52% of the variability in absolute endoxifen concentrations (31). Of particular note, for populations with a high frequency of the decreased function CYP2D6*10 allele, there was strong evidence that patients with CYP2D6 activity scores of 0 to 1 had significantly lower plasma endoxifen concentrations compared to those with normal CYP2D6 activity (AS=1.5 and 2).
Pharmacodynamic markers (Ki–67)—One prospective clinical study examined the association between CYP2D6 genotype and change in tumor Ki-67, a phenotype linked to drug efficacy, in patients with early stage breast cancer receiving neoadjuvant tamoxifen. In
A uthor Man uscr ipt A uthor Man uscr ipt A uthor Man uscr ipt A uthor Man uscr ipt
this study, patients with CYP2D6*10/*10 and CYP2D6*5/*10 genotypes had significantly lower Ki-67 response compared to patients genotyped as CYP2D6*1/*1 (42).
Breast cancer recurrence and survival—Because of the extensive biological variability across the various clinical settings where tamoxifen is administered (prevention, ductal carcinoma in situ, premenopausal and postmenopausal adjuvant setting, and metastatic), the current CPIC guidelines focuses only on the role of CYP2D6 genotype in the adjuvant treatment of ER+ breast cancer, using the endpoints of recurrence, recurrence- free survival, disease-free survival, distant relapse-free survival, breast cancer specific survival, and overall survival. The body of evidence for each of these clinical endpoints is summarized in Table S2. For the clinical endpoints of recurrence and event free-survival, the evidence was graded as moderate for the statements that CYP2D6 PMs (AS=0) have a higher risk of recurrence or worse event free survival. However, for the comparison of other metabolizer groups (IM, NM, and UM) and other clinical endpoints, the evidence was considered weak regarding an association between CYP2D6 metabolizer groups and clinical outcome (Table S2).
Therapeutic Recommendations
Table 2 summarizes the therapeutic recommendations for tamoxifen prescribing based on CYP2D6 phenotype. Based on current evidence (Table S2), CYP2D6 UMs and NMs are expected to achieve therapeutic endoxifen concentrations after administration of tamoxifen and should receive the recommended standard of care doses of tamoxifen. CYP2D6 PMs and IMs (including patients with an activity score of 1.0, see Supplement) are expected to have lower endoxifen concentrations compared to NMs and have a higher risk of breast cancer recurrence, and worse event-free survival compared to NMs. For CYP2D6 PMs, a
“strong” therapeutic recommendation was provided to recommend alternative hormonal therapy such as an aromatase inhibitor for postmenopausal women or aromatase inhibitor along with ovarian function suppression in premenopausal women given that these
approaches are superior to tamoxifen regardless of CYP2D6 genotype (43, 44) and based on knowledge that CYP2D6 PMs patients who switch from tamoxifen to anastrozole do not exhibit an increased risk of recurrence (38). Given that escalation of tamoxifen dose from 20–40 mg/day in CYP2D6 PM significantly increases endoxifen concentrations (but not to concentrations achieved in CYP2D6 NMs (45)), the use of an aromatase inhibitor (+/−
ovarian function suppression) is recommended in this setting. Tamoxifen 40 mg/day can be considered for CYP2D6 PM if there are contraindications to AI use. There are no clinical data that toremifene, another selective estrogen receptor modulator that also undergoes bioactivation (46), should be substituted for tamoxifen based on CYP2D6 genotype.
For CYP2D6 IMs and CYP2D6*10/*10 or CYP2D6*10/decreased function allele, a
“moderate” recommendation was made to consider use of an alternative hormonal therapy (i.e. aromatase inhibitor) for postmenopausal women or aromatase inhibitor plus ovarian function suppression in premenopausal women is recommended. In CYP2D6 IMs, if aromatase inhibitors are contraindicated, consideration can be given for the use of a higher FDA-approved dose of tamoxifen (40 mg/day), which is known to result in significantly higher endoxifen concentrations without an increase in toxicity (45). Based on extrapolation
A uthor Man uscr ipt A uthor Man uscr ipt A uthor Man uscr ipt A uthor Man uscr ipt
from evidence in *10 individuals, a similar recommendation applies to individuals who carry other decreased function alleles resulting in an activity score of 1.0 but with an “optional”
recommendation, given the paucity of data for this group.
In general, prolonged overlap of tamoxifen with strong and moderate CYP2D6 inhibitors should be avoided in tamoxifen-treated patients (47), whereas weak inhibitors are also contraindicated in CYP2D6 IMs.
Recommendations for Incidental Findings Not applicable
Other considerations
Pharmacogenetic variation in other cytochrome P450 genes such as CYP2C9 and CYP3A4 or CYP3A5 is associated with a small effect on plasma concentrations of both 4HT and endoxifen with unclear effects on clinical efficacy of tamoxifen. CYP2C19 genotype has also been associated with therapy outcome, where IMs and PMs showed an increased survival (HR 0.70), and direct effects on endoxifen plasma concentrations were described (48–51). Possibly, there is also an increase in tamoxifen drug concentrations, as recently suggested (52). While a meta-analysis demonstrated an association between CYP2C19 genotype and increased survival in tamoxifen treated breast cancer patients (53), an analysis of the International Tamoxifen Consortium dataset failed to find this correlation (54), leaving the clinical role of CYP2C19 genotyping for tamoxifen therapy unclear at the moment.
Implementation of this guideline—The guideline supplement contains resources that can be used within electronic health records (EHRs) to assist clinicians in applying genetic information to patient care for the purpose of drug therapy optimization (see Resources to incorporate pharmacogenetics into an electronic health record with clinical decision support sections of Supplement and the CPIC website (6)).
POTENTIAL BENEFITS AND RISKS FOR THE PATIENT
The potential benefit of using CYP2D6 genotype to guide tamoxifen use is that patients with genotypes that are associated with a higher risk of breast cancer recurrence, event-free survival (e.g., CYP2D6 IMs and PMs) may be identified and alternative doses (e.g. 40 mg) and agents administered. Given that the alternative drug treatments (aromatase inhibitors either with or without ovarian function suppression) have been demonstrated to be superior to tamoxifen (44, 43), and that CYP2D6 PMs switched from tamoxifen to anastrozole do not exhibit an increased risk of recurrence (38), it is expected the risks to use CYP2D6
genotyping to guide hormonal treatment would be low. Further research is necessary, however, to determine whether CYP2D6 genotypes associated with therapeutic endoxifen concentrations (e.g., NMs and UMs) should be preferentially maintained on tamoxifen. As with any laboratory test, a possible risk to patients is an error in genotyping or phenotype prediction, along with the presence of a rare genomic variant not tested for, which could have long-term adverse health implications for patients.
A uthor Man uscr ipt A uthor Man uscr ipt A uthor Man uscr ipt A uthor Man uscr ipt
CAVEATS: APPROPRIATE USE AND/OR POTENTIAL MISUSE OF GENETIC TESTS
Rare CYP2D6 variants may not be included in the genotype test used and patients with rare variants may be assigned a "wild-type" (CYP2D6*1) genotype by default. Thus, an assigned
“wild-type” allele could potentially harbor a no or decreased function variant. Therefore, it is important that test reports do include information on which variant alleles were tested.
Furthermore, it is important that the genetic testing platform includes testing for gene copy number.
Like all diagnostic tests, CYP2D6 genotype is one of multiple pieces of information that clinicians should consider when making their therapeutic choice for each patient. For example, for the treatment of ER+ breast cancer, there are well accepted tumor somatic factors that drive endocrine response, including the tumor expression of ER, PR and HER2 expression, and other multigene assays which are associated with endocrine sensitivity (55).
Although there are very few data, the implication of reduced CYP2D6 metabolism in patients with low risk breast cancer (e.g., early stage breast cancer where the risk of distant recurrence is low) may be substantially different than in patients with later stage disease with a much higher risk of distant recurrence.
DISCLAIMER
Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines reflect expert consensus based on clinical evidence and peer-reviewed literature available at the time they are written and are intended only to assist clinicians in decision-making, as well as to identify questions for further research. New evidence may have emerged since the time a guideline was submitted for publication. Guidelines are limited in scope and are not applicable to interventions or diseases not specifically identified. Guidelines do not account for all individual variation among patients and cannot be considered inclusive of all proper methods of care or exclusive of other treatments. It remains the responsibility of the health care provider to determine the best course of treatment for the patient. Adherence to any guideline is voluntary, with the ultimate determination regarding its application to be solely made by the clinician and the patient. CPIC assumes no responsibility for any injury to persons or damage to property related to any use of CPIC's guidelines, or for any errors or omissions.
Supplementary Material
Refer to Web version on PubMed Central for supplementary material.
Acknowledgments
We acknowledge the critical input of Dr. M. Relling and members of the Clinical Pharmacogenetics Implementation Consortium of the Pharmacogenomics Research Network, funded by the National Institutes of Health.
FUNDING
A uthor Man uscr ipt A uthor Man uscr ipt A uthor Man uscr ipt A uthor Man uscr ipt
This work was funded by the National Institutes of Health (NIH) for CPIC (R24GM115264), PharmGKB (R24GM61374) and PharmVar (R24 GM123930). M.S. is supported by grants of the German Federal Ministry of Education and Research (BMBF 01ZP0502 & 01EK1509A), the EU H2020 UPGx grant (668353) and the Robert Bosch Foundation, Stuttgart, Germany. Supported in part by Specialized Programs of Research Excellence Grants No. P50CA 116201 (M.P.G., J.N.I.).
References
1. PharmGKB. [Accessed September 16 2016] Gene Reference Materials for CYP2D6. <https://
www.pharmgkb.org/page/cyp2d6RefMaterials>
2. Crews KR, et al. Clinical Pharmacogenetics Implementation Consortium guidelines for cytochrome P450 2D6 genotype and codeine therapy: 2014 update. Clin Pharmacol Ther. 2014; 95:376–82.
[PubMed: 24458010]
3. Gaedigk A, Simon SD, Pearce RE, Bradford LD, Kennedy MJ, Leeder JS. The CYP2D6 activity score: translating genotype information into a qualitative measure of phenotype. Clin Pharmacol Ther. 2008; 83:234–42. [PubMed: 17971818]
4. Crews KR, et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines for codeine therapy in the context of cytochrome P450 2D6 (CYP2D6) genotype. Clin Pharmacol Ther.
2012; 91:321–6. [PubMed: 22205192]
5. Hicks JK, et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2D6 and CYP2C19 Genotypes and Dosing of Selective Serotonin Reuptake Inhibitors. Clin Pharmacol Ther. 2015; 98:127–34. [PubMed: 25974703]
6. CPIC. CPIC Guideline for Tamoxifen based on CYP2D6 genotype. <htpps://cpicpgx.org/cpic- guideline-for-tamoxifen-based-on-cyp2d6-genotype>
7. Goetz MP, et al. Loss of heterozygosity at the CYP2D6 locus in breast cancer: implications for germline pharmacogenetic studies. J Natl Cancer Inst. 2014; 107
8. Johnson JA, Hamadeh IS, Langaee TY. Loss of heterozygosity at the CYP2D6 locus in breast cancer: implications for tamoxifen pharmacogenetic studies. J Natl Cancer Inst. 2015; 107 9. Li CI, Daling JR, Malone KE. Incidence of invasive breast cancer by hormone receptor status from
1992 to 1998. J Clin Oncol. 2003; 21:28–34. [PubMed: 12506166]
10. Davies C, et al. Relevance of breast cancer hormone receptors and other factors to the efficacy of adjuvant tamoxifen: patient-level meta-analysis of randomised trials. Lancet. 2011; 378:771–84.
[PubMed: 21802721]
11. Wu X, Hawse JR, Subramaniam M, Goetz MP, Ingle JN, Spelsberg TC. The tamoxifen metabolite, endoxifen, is a potent antiestrogen that targets estrogen receptor alpha for degradation in breast cancer cells. Cancer Res. 2009; 69:1722–7. [PubMed: 19244106]
12. Jordan VC. New insights into the metabolism of tamoxifen and its role in the treatment and prevention of breast cancer. Steroids. 2007; 72:829–42. [PubMed: 17765940]
13. Osborne CK, et al. Role of the estrogen receptor coactivator AIB1 (SRC-3) and HER-2/neu in tamoxifen resistance in breast cancer. J Natl Cancer Inst. 2003; 95:353–61. [PubMed: 12618500]
14. Shang Y, Brown M. Molecular determinants for the tissue specificity of SERMs. Science. 2002;
295:2465–8. [PubMed: 11923541]
15. Tseng E, et al. Relative contributions of cytochrome CYP3A4 versus CYP3A5 for CYP3A-cleared drugs assessed in vitro using a CYP3A4-selective inactivator (CYP3cide). Drug Metab Dispos.
2014; 42:1163–73. [PubMed: 24737844]
16. Desta Z, Ward BA, Soukhova NV, Flockhart DA. Comprehensive evaluation of tamoxifen sequential biotransformation by the human cytochrome P450 system in vitro: prominent roles for CYP3A and CYP2D6. The Journal of pharmacology and experimental therapeutics. 2004;
310:1062–75. [PubMed: 15159443]
17. Murdter TE, et al. Activity levels of tamoxifen metabolites at the estrogen receptor and the impact of genetic polymorphisms of phase I and II enzymes on their concentration levels in plasma.
Clinical pharmacology and therapeutics. 2011; 89:708–17. [PubMed: 21451508]
18. Sanchez Spitman AB, Moes D, Gelderblom H, Dezentje VO, Swen JJ, Guchelaar HJ. Effect of CYP3A4*22, CYP3A5*3, and CYP3A combined genotypes on tamoxifen metabolism. Eur J Clin
A uthor Man uscr ipt A uthor Man uscr ipt A uthor Man uscr ipt A uthor Man uscr ipt
19. Jordan VC, Collins MM, Rowsby L, Prestwich G. A monohydroxylated metabolite of tamoxifen with potent antioestrogenic activity. J Endocrinol. 1977; 75:305–16. [PubMed: 591813]
20. Allen KE, Clark ER, Jordan VC. Evidence for the metabolic activation of non-steroidal antioestrogens: a study of structure-activity relationships. Br J Pharmacol. 1980; 71:83–91.
[PubMed: 7470748]
21. Borgna JL, Rochefort H. Hydroxylated metabolites of tamoxifen are formed in vivo and bound to estrogen receptor in target tissues. J Biol Chem. 1981; 256:859–68. [PubMed: 7451477]
22. Stearns V, et al. Active tamoxifen metabolite plasma concentrations after coadministration of tamoxifen and the selective serotonin reuptake inhibitor paroxetine. J Natl Cancer Inst. 2003;
95:1758–64. [PubMed: 14652237]
23. Johnson MD, et al. Pharmacological characterization of 4-hydroxy-N-desmethyl tamoxifen, a novel active metabolite of tamoxifen. Breast Cancer Res Treat. 2004; 85:151–9. [PubMed:
15111773]
24. Lim YC, Desta Z, Flockhart DA, Skaar TC. Endoxifen (4-hydroxy-N-desmethyl-tamoxifen) has anti-estrogenic effects in breast cancer cells with potency similar to 4-hydroxy-tamoxifen. Cancer Chemother Pharmacol. 2005; 55:471–8. [PubMed: 15685451]
25. Maximov PY, et al. Simulation with cells in vitro of tamoxifen treatment in premenopausal breast cancer patients with different CYP2D6 genotypes. Br J Pharmacol. 2014; 171:5624–35. [PubMed:
25073551]
26. Maximov PY, et al. Pharmacological relevance of endoxifen in a laboratory simulation of breast cancer in postmenopausal patients. Journal of the National Cancer Institute. 2014; 106
27. Lonning PE, Lien EA, Lundgren S, Kvinnsland S. Clinical pharmacokinetics of endocrine agents used in advanced breast cancer. Clin Pharmacokinet. 1992; 22:327–58. [PubMed: 1505141]
28. Ingle JN, et al. Evaluation of tamoxifen plus letrozole with assessment of pharmacokinetic interaction in postmenopausal women with metastatic breast cancer. Clin Cancer Res. 1999;
5:1642–9. [PubMed: 10430063]
29. Jin Y, et al. CYP2D6 genotype, antidepressant use, and tamoxifen metabolism during adjuvant breast cancer treatment. J Natl Cancer Inst. 2005; 97:30–9. [PubMed: 15632378]
30. Safgren SL, et al. Evaluation of CYP2D6 enzyme activity using a 13C-dextromethorphan breath test in women receiving adjuvant tamoxifen. Pharmacogenetics and genomics. 2015; 25:157–63.
[PubMed: 25714002]
31. Schroth W, et al. Improved Prediction of Endoxifen Metabolism by CYP2D6 Genotype in Breast Cancer Patients Treated with Tamoxifen. Front Pharmacol. 2017; 8:582. [PubMed: 28955222]
32. Goetz MP, et al. Pharmacogenetics of tamoxifen biotransformation is associated with clinical outcomes of efficacy and hot flashes. J Clin Oncol. 2005; 23:9312–8. [PubMed: 16361630]
33. Schroth W, et al. Breast cancer treatment outcome with adjuvant tamoxifen relative to patient CYP2D6 and CYP2C19 genotypes. J Clin Oncol. 2007; 25:5187–93. [PubMed: 18024866]
34. Schroth W, et al. Association between CYP2D6 polymorphisms and outcomes among women with early stage breast cancer treated with tamoxifen. Jama. 2009; 302:1429–36. [PubMed: 19809024]
35. US Food and Drug Administration: Summary minutes of the advisory committee pharmaceutical science, clinical pharmacology subcommittee, October 18–19, 2006. <http://www.fda.gov/ohrms/
dockets/ac/06/minutes/2006-4248m1.pdf>
36. Rae JM, et al. CYP2D6 and UGT2B7 Genotype and Risk of Recurrence in Tamoxifen-Treated Breast Cancer Patients. Journal of the National Cancer Institute. 2012; 104:452–60. [PubMed:
22395643]
37. Regan MM, et al. CYP2D6 Genotype and Tamoxifen Response in Postmenopausal Women with Endocrine-Responsive Breast Cancer: The Breast International Group 1–98 Trial. Journal of the National Cancer Institute. 2012; 104:441–51. [PubMed: 22395644]
38. Goetz MP, et al. CYP2D6 metabolism and patient outcome in the Austrian Breast and Colorectal Cancer Study Group trial (ABCSG) 8. Clin Cancer Res. 2013; 19:500–7. [PubMed: 23213055]
39. Province MA, et al. CYP2D6 genotype and adjuvant tamoxifen: meta-analysis of heterogeneous study populations. Clinical pharmacology and therapeutics. 2014; 95:216–27. [PubMed:
24060820]
A uthor Man uscr ipt A uthor Man uscr ipt A uthor Man uscr ipt A uthor Man uscr ipt
40. Madlensky L, et al. Tamoxifen metabolite concentrations, CYP2D6 genotype, and breast cancer outcomes. Clin Pharmacol Ther. 2011; 89:718–25. [PubMed: 21430657]
41. Saladores P, et al. Tamoxifen metabolism predicts drug concentrations and outcome in
premenopausal patients with early breast cancer. Pharmacogenomics J. 2015; 15:84–94. [PubMed:
25091503]
42. Zembutsu H, et al. Significant Effect of Polymorphisms in CYP2D6 on Response to Tamoxifen Therapy for Breast Cancer: A Prospective Multicenter Study. Clin Cancer Res. 2017; 23:2019–26.
[PubMed: 27797974]
43. Early Breast Cancer Trialists' Collaborative, G. Aromatase inhibitors versus tamoxifen in early breast cancer: patient-level meta-analysis of the randomised trials. Lancet. 2015; 386:1341–52.
[PubMed: 26211827]
44. Pagani O, et al. Adjuvant exemestane with ovarian suppression in premenopausal breast cancer. N Engl J Med. 2014; 371:107–18. [PubMed: 24881463]
45. Hertz DL, et al. Tamoxifen Dose Escalation in Patients With Diminished CYP2D6 Activity Normalizes Endoxifen Concentrations Without Increasing Toxicity. Oncologist. 2016; 21:795–
803. [PubMed: 27226358]
46. Kim J, et al. Role and pharmacologic significance of cytochrome P-450 2D6 in oxidative metabolism of toremifene and tamoxifen. Int J Cancer. 2013; 132:1475–85. [PubMed: 22915089]
47. Hansten, PD., Horn, JR. Top 100 Drug Interactions 2017: A Guide to Patient Management. 1. H &
H Publicatgions, LLP; Freeland: 2017.
48. Ruiter R, et al. CYP2C19*2 polymorphism is associated with increased survival in breast cancer patients using tamoxifen. Pharmacogenomics. 2010; 11:1367–75. [PubMed: 21047200]
49. van Schaik RH, et al. The CYP2C19*2 genotype predicts tamoxifen treatment outcome in advanced breast cancer patients. Pharmacogenomics. 2011; 12:1137–46. [PubMed: 21830868]
50. Beelen K, et al. CYP2C19 2 predicts substantial tamoxifen benefit in postmenopausal breast cancer patients randomized between adjuvant tamoxifen and no systemic treatment. Breast Cancer Res Treat. 2013; 139:649–55. [PubMed: 23736997]
51. Lim JS, et al. Association of CYP2C19*2 and associated haplotypes with lower norendoxifen concentrations in tamoxifen-treated Asian breast cancer patients. Br J Clin Pharmacol. 2016;
81:1142–52. [PubMed: 26799162]
52. Powers JL, et al. Multigene and Drug Interaction Approach for Tamoxifen Metabolite Patterns Reveals Possible Involvement of CYP2C9, CYP2C19, and ABCB1. J Clin Pharmacol. 2016;
56:1570–81. [PubMed: 27198207]
53. Bai L, He J, He GH, He JC, Xu F, Xu GL. Association of CYP2C19 polymorphisms with survival of breast cancer patients using tamoxifen: results of a meta-analysis. Asian Pac J Cancer Prev.
2014; 15:8331–5. [PubMed: 25339025]
54. Damkier P, et al. CYP2C19*2 and CYP2C19*17 variants and effect of tamoxifen on breast cancer recurrence: Analysis of the International Tamoxifen Pharmacogenomics Consortium dataset. Sci Rep. 2017; 7:7727. [PubMed: 28798474]
55. Paik S, et al. A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer. N Engl J Med. 2004; 351:2817–26. [PubMed: 15591335]
56. Goetz MP, et al. CYP2D6 metabolism and patient outcome in the Austrian Breast and Colorectal Cancer Study Group trial (ABCSG) 8. Clin Cancer Res. 2013; 19:500–7. [PubMed: 23213055]
57. Klein DJ, Thorn CF, Desta Z, Flockhart DA, Altman RB, Klein TE. PharmGKB summary:
tamoxifen pathway, pharmacokinetics. Pharmacogenet Genomics. 2013; 23:643–7. [PubMed:
23962908]
A uthor Man uscr ipt A uthor Man uscr ipt A uthor Man uscr ipt A uthor Man uscr ipt
Figure 1.
Tamoxifen Pathway, Pharmacokinetics (57). Permission has been given by PharmGKB and Stanford to use figure.
A uthor Man uscr ipt A uthor Man uscr ipt A uthor Man uscr ipt A uthor Man uscr ipt
A uthor Man uscr ipt A uthor Man uscr ipt A uthor Man uscr ipt A uthor Man uscr
Table 1 Assignment of Likely Phenotypes Based on Diplotypes
Phenotypea Genotype Examples of CYP2D6
diplotypesb
Metabolizer Activity Score
CYP2D6 Ultrarapid metabolizer > 2.0 An individual carrying duplications of
functional alleles *1/*1xN, *1/*2xN, *2/*2xNc
CYP2D6 Normal metabolizer 1.5 and 2.0 An individual carrying two normal function alleles or one normal function and one decreased function allele
*1/*1, *1/*2, *1/*9, *1/*41, *2/*2,
CYP2D6 Normal metabolizeror Intermediate metabolizer (controversy remains)d
1.0 An individual carrying two decreased function alleles or one normal function and one no function allele.
*1/*4, *1/*5, *41/*41
An activity score (AS) of 1.0 is associated with decreased tamoxifen metabolism to endoxifen compared to those with an AS of 1.5 or 2.
CYP2D6 Intermediate metabolizer 0.5 An individual carrying one decreased function and one no function allele
*4/*10,*4/*41, *5/*9
CYP2D6 Poor metabolizer 0 An individual carrying only no
functional alleles
*3/*4,*4/*4, *5/*5, *5/*6
aSee the CYP2D6 frequency table (1) for race-specific allele and phenotype frequencies.
bFor a complete list of CYP2D6 diplotypes and resulting phenotypes, see the CYP2D6 genotype to phenotype table (1, 6). Note that genotypes with an activity score of 1 are classified as NMs in the online CYP2D6 genotype to phenotype table.
cWhere xN represents the number of CYP2D6 gene copies. For individuals with CYP2D6 duplications or multiplications, see supplemental data for additional information on how to translate diplotypes into phenotypes.
dPatients with an activity score of 1.0 may be classified as intermediate metabolizers by some reference laboratories. A group of CYP2D6 experts are currently working to standardize the CYP2D6 genotype to phenotype translation system. CPIC will update the CPIC website accordingly (CYP2D6 genotype to phenotype table (1, 6)).
A uthor Man uscr ipt A uthor Man uscr ipt A uthor Man uscr ipt A uthor Man uscr ipt
Table 2
Dosing Recommendations for tamoxifen based on CYP2D6 phenotype
Phenotype Implications Therapeutic Recommendationb Classification of
Recommendationa Metabolizer Status Activity Score
CYP2D6 Ultrarapid metabolizer >2.0 Therapeutic endoxifen concentrations Avoid moderate and strong CYP2D6 inhibitors. Initiate therapy with recommended standard of care dosing (tamoxifen 20 mg/day).
Strong
CYP2D6 Normal metabolizer 1.5 to 2.0 Therapeutic endoxifen concentrations Avoid moderate and strong CYP2D6 inhibitors. Initiate therapy with recommended standard of care dosing (tamoxifen 20 mg/day).
Strong
CYP2D6 Normal metabolizeror Intermediate metabolizer (controversy remains)b
1.0 (no *10 allele present)b
Lower endoxifen concentrations compared to normal metabolizers;
higher risk of breast cancer recurrence, event-free and recurrence-free survival compared to normal metabolizers.
Consider hormonal therapy such as an aromatase inhibitor for postmenopausal women or aromatase inhibitor along with ovarian function suppression in premenopausal women, given that these approaches are superior to tamoxifen regardless of CYP2D6 genotype (43). If aromatase inhibitor use is contraindicated, consideration should be given to use a higher but FDA approved tamoxifen dose (40 mg/day)(45). Avoid CYP2D6 strong to weak inhibitors.
Optionalb
CYP2D6 Normal metabolizeror Intermediate metabolizer (controversy remains)b
1.0 (*10 allele present)b
Lower endoxifen concentrations compared to normal metabolizers;
higher risk of breast cancer recurrence, event-free and recurrence-free survival compared to normal metabolizers.
Consider hormonal therapy such as an aromatase inhibitor for postmenopausal women or aromatase inhibitor along with ovarian function suppression in premenopausal women, given that these approaches are superior to tamoxifen regardless of CYP2D6 genotype (43). If aromatase inhibitor use is contraindicated, consideration should be given to use a higher but FDA approved tamoxifen dose (40 mg/day)(45). Avoid CYP2D6 strong to weak inhibitors.
Moderateb
CYP2D6 Intermediate metabolizer 0.5 Lower endoxifen concentrations compared to normal metabolizers;
higher risk of breast cancer recurrence, event-free and recurrence-free survival compared to normal metabolizers.
Consider hormonal therapy such as an aromatase inhibitor for postmenopausal women or aromatase inhibitor along with ovarian function suppression in premenopausal women, given that these approaches are superior to tamoxifen regardless of CYP2D6 genotype (43). If aromatase inhibitor use is contraindicated, consideration should be given to use a higher but FDA approved tamoxifen dose (40 mg/day)(45). Avoid CYP2D6 strong to weak inhibitors.
Moderate
CYP2D6 Poor metabolizer 0 Lower endoxifen concentrations compared to normal metabolizers;
higher risk of breast cancer
Recommend alternative hormonal therapy such as an aromatase inhibitor for
Strong
A uthor Man uscr ipt A uthor Man uscr ipt A uthor Man uscr ipt A uthor Man uscr
Phenotype Implications Therapeutic Recommendationb Classification of
Recommendationa Metabolizer Status Activity Score
recurrence, event-free and recurrence-free survival compared to normal metabolizers.
postmenopausal women or aromatase inhibitor along with ovarian function suppression in premenopausal women given that these approaches are superior to tamoxifen regardless of CYP2D6 genotype (43) and based on knowledge that CYP2D6 poor metabolizers switched from tamoxifen to anastrozole do not have an increased risk of recurrence (38). Note, higher dose tamoxifen (40 mg/day) increases but does not normalize endoxifen concentrations and can be considered if there are contraindications to aromatase inhibitor therapy (45, 56).
aRating scheme described in Supplement.
bCPIC has generally classified patients with an activity score of 1 as a “normal metabolizer”. However, in the case of tamoxifen, prescribing recommendations for those with an AS of 1.0 are allele dependent, based on the presence of the *10 allele. Those patients with an AS of 1.0 on the basis a *10 allele are provided a “moderate,” recommendation. In contrast, prescribing recommendations for those with an activity score of 1 based on the presence of CYP2D6 alleles other than *10 are graded as “optional” because the recommendations are primarily extrapolated from evidence generated from *10 individuals (i.e. limited data for clinical outcomes and pharmacokinetics for this group).
